About 3 billion individuals around the world are at risk for malaria, there are about 250 million cases per year, with about 1 million deaths. While deployment of insecticide impregnated bed nets, new drug combinations, and possibly new vaccines may help control malaria, we hypothesize that shrinking parasite population sizes would place greater burdens on the pathogens to change at faster rates, possibly contributing to higher virulence. Initially, such evolution could be to overcome drugs and cause resistance. However, once the capacity for faster genetic change is in place, the traits may favor acquisition of new niches, within vectors (to favor propagation of the disease) and within human hosts (possibly presenting new disease presentations). This multicenter Program Project application will study the evolution of malaria parasites in South Asia. Malaria is not uniform across South Asia. One sees large variation in species-dominance from NE to Southern states, one sees frequent epidemics of severe malaria, sometimes for unexplained reasons. We hypothesize that South Asia harbors virulent forms of P. falciparum from SE Asia that display the Accelerated Resistance to Multiple Drugs (ARMD) phenotype. This may help ARMD P. falciparum over run traditional P. vivax. In addition to drug resistance, the transmission and virulence properties of sites harboring ARMD parasites, are expected to be different. The Program Director proposes a 5 project Center that touches on epidemiology, parasite plasticity, pathogenesis, transmission, and human genetics in South Asia. Research will be facilitated by scientific partnerships between physicians and academic researchers in India and the US, and by Administration, Data Management, and Statistical support from partners in Delhi and Kolkata. Parasites and their interactions with humans, and mosquitoes, will be studied in Assam and Tripura (near Myanmar), in Ranchi (proximal forested sites with highly endemic malaria), in Wardha in Central India, and finally in the Western cities of Mumbai and Goa (with urban malaria, low endemicity, and high human genetic diversity). The results will teach us about propagation of malaria across subcontinents, and about the possible barriers and breakdown of barriers against the spread of virulent malaria parasites.